The goal of this NINDS Faculty Development Award (K01) is to provide support and protected time for a junior faculty member to obtain independent research support while transitioning from a mentored position to an independent investigator in academic neuroscience. The proposed studies will provide new knowledge on the theory and methodological approaches for the application of translational science. In addition, these studies will provide training in the experimental aspects for studying tau prion-like behavior in tauopathies. The research proposed will be conducted under the mentoring of Dr. Holtzman, in which the candidate will investigate tau immunotherapies, gene therapy, and mechanisms by which tau propagates the spread of pathology. Although pathological tau is a central component of over 20 distinct neurodegenerative diseases there is currently no effective treatment for tauopathies. Recent studies from the Holtzman lab and others have demonstrated that passive immunizations using certain monoclonal antibodies (mABs) against tau are neuro-protective in mouse models of tauopathies. This evidence for the beneficial effects of tau immunotherapy warrants further investigation for improving the efficacy of tau immunotherapies and for determining a mode of delivery for long-term treatment. Furthermore, the emergence of tau as a target for immunotherapies together with recent studies demonstrating the phenomenon of spreading tau pathology raises the question whether the progression of tau pathology involves extracellular monomeric and possibly oligomer tau in the spreading of tau pathology. The goals of this project are to determine whether a combination of immunotherapy with gene therapy is a feasible approach for long-term treatment and to improve the efficacy of tau immunotherapy by determining the role of the immunoglobulin G (IgG) fragment crystallize (Fc) domain in the neuro-protective activity of anti-tau mABs in vivo. Additionally, we will determine whether tau in the extracellular space promotes the spread of tau pathology identifying a mechanism for tau prion-like behavior. To test the hypothesis that antibody-mediated decrease in tau pathology does not require anti-tau antibody Fc domain and that extracellular forms of tau mediate cell to cell tau spreading, we will examine the following Aims: 1: For long-term treatment of tauopathies we will develop a strategy for gene transfer delivery of anti-tau mABs in vivo. 2: To understand the efficacy of tau immunotherapy we will determine the roles for the immunoglobulin G (IgG) fragment crystalizable (Fc) domain effector function in tau immunotherapy in vivo. 3: To investigate tau prion-like behavior we will determine the contribution of extracellular tau in th spreading of tau pathology